Carcinoma of the prostate (CaP) is the second leading cause of cancer-related death in men. Reportedly, there were an estimated 221,000 new cases of CaP diagnosed in 2003 with an estimated 28,900 deaths. See American Cancer Society, Key Statistics about Prostate Cancer 2003; Jemal et al., CA Cancer J. Clin., 52:23-47 (2002). CaP presents a relatively high rate of morbidity and mortality necessitating prompt detection and effective treatment.
CaP has been commonly treated with surgery, i.e., radical prostatectomy. This procedure presents drawbacks in terms of surgical risks and impairment, and additionally, its usefulness may be limited to early-stage, organ-confined cancers. In advanced cases, the cancer may have spread beyond the bounds of the removed tissue, making it unlikely surgery will be a successful treatment. Radiation therapy also has been widely used as an alternative and/or supplement to surgery but with limited success.
In recent years, various treatment strategies have focused on inhibiting the role of androgens [testosterone (T) and dihydrotestosterone (DHT)] in prostate tumor growth. The androgen receptor (AR) is a ligand-binding transcription factor in the nuclear-hormone receptor (NHR) superfamily, and it is an important mediator of prostate cancer development and growth. The androgens (T and DHT) compete for binding to the AR (DHT having a higher binding affinity than T), and both T and DHT activate the AR, influencing cell function and stimulating growth of the prostate and other tissue, including prostate tumor cells.
Recent efforts for treating CaP have focused on developing compounds that act as androgen receptor modulators. A compound that binds to the AR and mimics the effect of the natural ligand (e.g., T or DHT) is referred to as an “agonist”, while a compound that inhibits the effect of a natural ligand in binding to the AR is referred to as an “antagonist”. AR antagonist and/or agonists (collectively “antiandrogens”) have proven useful in the treatment of CaP.
However, AR is related to other members of the subfamily of NHR's, which share a sequence homology to one another. Other members of this sub-family include the estrogen receptor (ER), the progesterone receptor (PR), the glucocorticoid receptor (GR), the mineralcorticoid receptor (MR), and the aldosterone receptor (ALDR). Ligands to these receptors are known to play an important role in the health of men and women. Given the similarity in sequence homology of these NHR's, the development of compounds which have good specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid receptors (thus reducing or avoiding undesirable side effects), has presented challenges. There are several known, approved non-steroidal antiandrogens including bicalutamide, Eulexin, and Anandrone. However, these antiandrogens may bind reversibly to the AR, and if treatment is continued for a period of years, tumors may become androgen independent. Androgen-independent tumors are not affected by the natural ligands (T and DHT), and thus, antiandrogens may lose effectiveness in treating androgen-independent tumors.
As may be appreciated, there remains a need for more potent AR antagonists and/or AR antagonist with a different pharmacological profile as compared with currently-known antiandrogens.